This proposal aims to identify the role of CNS alterations in the etiology of altered visceral perception and autonomic function underlying the chronic abdominal pain/discomfort of patients with the Irritable Bowel Syndrome (IBS). Since no animal models of IBS are available, little progress has been made in the characterization of possible CNS alterations in IBS. Functional brain imaging using positron emission tomography (PET) has made it possible to study the living human brain non-invasively, and to identifY possible brain correlates of visceral pain and of associated autonomic responses. Using with H2/15/0 PET and psychophysical techniques, the current proposal will test the following 3 hypotheses (each addressed in a Specific Aim): 1) IBS is associated with disease-specific perceptual alterations of noxious visceral stimuli and distinct patterns of associated autonomic responses, which are present either under baseline conditions, or are inducible by repetitive sigmoid stimulation. 2) IBS patients show a specific alteration in regional brain activity during rectosigmoid pain and its anticipation. 3) The correlation between regional cerebral activity and perceptual and autonomic responses to rectosigmoid pain or its anticipation is altered in IBS patients. We will test these hypotheses by comparing IBS patients to 2 control groups (healthy controls and patients with inflammatory bowel disease, IBD) in their physiologic and subjective responses to acute rectosigmoid mechanical stimulation performed using a double balloon catheter, inflated by a computerized distension device. Regional cerebral blood flow (rCBF) changes will be measured using H2/15/0 PET. Autonomic responses (skin conductance, finger pulse amplitude, heart rate, vagal tone)in response to visceral pain and its anticipation will be recorded. In Aim 1 we will first characterize alterations in basal rectal perception by evaluating thresholds for affective pain ratings, and stimulus-response functions for sensory aspects of pain. To determine if the perceptual alteration is limited to the intestine, we will also assess pain perception in the esophagus and in thoracolumbar and cervical dermatomes. We will then study the perceptual (rectal, esophageal and somatic) and autonomic responses to prolonged repetitive sigmoid distension, a paradigm that results in rectal hyperalgesia in IBS patients. To test the hypothesis that the differential response to sigmoid stimulation is related to the activation of opioid-mediated endogenous pain inhibition systems, we will evaluate the effect of naloxone on perceptual and autonomic responses in the three clinical groups. By comparing responses obtained in patients during clinical remission with those obtained during symptom exacerbation, we will evaluate for effects of disease on individual nociceptive responses. In Aim 2, we will determine rCBF changes in response to painful and non- painful rectal distension following sigmoid sensitization. By restudying patients longitudinally during symptomatic and asymptomatic periods, we will evaluate whether disease activity correlates with brain alterations. In Aim 3, we will determine if perceptual and autonomic responses to rectal pain stimuli and anticipation of pain correlate with rCBF alterations in specific brain areas. Preliminary results are provided which demonstrate that all proposed aims are feasible, and all proposed hypotheses testable. The proposed studies will for the first time allow the characterization of altered brain function in IBS patients and correlation of these alterations with clinical parameters, in response to acute visceral pain. Once such alterations are identified, they may provide reliable physiological markers and therapeutic targets in the future.